A sparsely populated user fee calendar for the remainder of 2011 likely precludes a repeat of FDA’s stunning approval performance in the first half of this year. Still, with 20 approvals of new molecular entities and novel biologics during those first six months, the agency is all but assured of one of its best years in a decade – at the least.

The number of approvals is startling after a decade of anemic novel approval totals, but it’s not the only notable aspect of FDA’s first half 2011 approvals. CDER, which drove the rally, also posted excellent numbers on key review performance and efficiency markers: time to approval, first cycle approvals, and approvals meeting their PDUFA goal date. In fact, FDA met the PDUFA goal date for an unprecedented 100% of its first-half approvals.

In the first six months of the year, CDER approved 18 novel agents – 15 NMEs and three novel biologics. It posted low review times of 12.9 months for NMEs and 13.8 months for therapeutic biologics, and cleared two-thirds of its approvals in one review cycle, the highest level in 20 years.

FDA's review metrics also stand out, meeting an unprecedented 100% of user fee goal dates with low average review times.

The excellent first half approval total, built on exemplary review management performance, proved very well-timed for CDER Director Janet Woodcock as Congress opened debate on the reauthorization of the Prescription Drug User Fee Act with a House subcommittee hearing July 7. She highlighted the large number of approvals and the record-high rate of first cycle approvals to rebut critics who accuse the agency of stifling innovation and investment (Also see "Woodcock Defends Speed Of FDA Reviews, Cites 20 Approvals In First Half Of 2011" - Pink Sheet, 7 July, 2011.).

While the first half 2011 tally starkly contrasts with 2010, the agency’s review management performance continues, or accelerates, positive trends in review time and efficiency seen in the prior year.

Office of New Drugs Director John Jenkins has championed improvements in the process of reviewing new drug reviews, focusing on a well-managed and efficient process (Also see "Few, But Fast And On Time: 2010 Saw Low NMEs, But Almost All Were First-Cycle Approvals And FDA Met Most User Fees" - Pink Sheet, 1 January, 2011.). Those efforts appear to be paying off in terms of shorter and more predictable times from submission to approval.

But even the most perfectly managed review team cannot approve new drugs without NDAs and BLAs to review, and the dwindling supply of applications is likely to dampen the approval pace for the rest of 2011.

All Dressed Up, With Few Drugs To Review

The sizzling first half pace, more reminiscent of the 1990s boom years than the meager approval counts since, means that FDA should have little trouble matching or surpassing most of the years of the last decade, where NME approval totals have languished in the high teens to low 20s (see chart).

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[To view chart in full size, click here.]

CDER’s 15 NME approvals in the first half already matches the full-year NME total for 2010. And two NMEs approved on July 1 – Novartis’ Arcapta Neohaler (indacaterol) and Johnson & Johnson/Bayer’s Xarelto (rivaroxaban) – meant CDER has already this year matched the 17 approvals in all of 2002 and exceeded 2007’s 16 NME clearances.

Despite this pace, the full-year count for 2011 may still fall short of the most recent 12-month NME approval high points – the 31 approvals posted in 2004 and the 27 in 2000.

FDA’s performance throughout the year is driven by when sponsors submit applications, so lopsided counts are not unusual. In 2008, for example, CDER also cleared 15 NMEs in the latter six months of the year, but with a low six NME clearances in the first half the agency only posted 21 approvals for the full year.

There are only about a dozen novel agents, both NMEs and BLAs, with user fee goals in the second half of 2011 (see chart, Also see "Novel & Significant Applications With Second Half 2011 User Fee Goals" - Pink Sheet, 1 July, 2011.).

The make-up of the second half 2011 class is not unusual. One-third of the upcoming user fee goal dates are for biologics. Five are for oncologics, consistently the most active therapeutic area, including hotly anticipated candidates from Pfizer (crizotinib for non-small cell lung cancer), Incyte (ruxolitinib for myelofibrosis), Genentech and Plexxikon (vemurafenib for melanoma) and Seattle Genetics (brentuximab vedotin for Hodgkin lymphoma and anaplastic large-cell lymphoma).

Consistency In 2011 Approvals To Date

The current state of affairs bears out Woodcock’s recent assertion that FDA, despite its faults, is the most predictable part of the process of bringing a new drug to approval (Also see "FDA Still Most Predictable Part of Drug Development, Despite Bumps, Woodcock Says" - Pink Sheet, 1 June, 2011.). CDER has been conducting reviews within the PDUFA goal timeframe, with a high rate of first-cycle approvals and an average time to approval at the low end of the usual range. And the low number of pending applications reflects the hazards of R&D on the industry side.

FDA has been very consistent about review times, which is especially notable in multi-cycle reviews, where the ball returns to the sponsor’s court.

Only one-third of CDER approvals required more than one review cycles, and none have required more than two. The approval times were all close to the average of 22.5 months; the longest review, for GlaxoSmithKline/Xenoport’s Horizant (gabapentin enacarbil) for restless leg syndrome, clocked in at a less-than-epic 26.9 months. In comparison, Chemische Fabrik Kreussler Asclera (polidocanol), the longest review in 2010, spent more than five years from submission to approval.

CDER’s 100% on-time review performance in the first half, topping 2010’s earlier record 86% rate, suggests that OND Director Jenkins’ strategy for dealing with increased review demands in the wake of FDAAA is yielding success. Between November 2007 and October 2009, Jenkins de-prioritized meeting PDUFA review goals as FDA adjusted to FDAAA changes. On-time approval percentages dipped during the interregnum, with only 76% of 2008 NMEs and 64% of 2009 NMEs cleared by their user fee goals, but came roaring back in 2010 with 87% of NMEs approved on time and 100% in 2011 so far.

Big Pharma Is Back

Almost half of the 20 FDA novel approvals through June were for products sponsored by a big pharma firm. Johnson & Johnson and GlaxoSmithKline both received three novel agent approvals in the first half of 2011 (rebounding from no approvals for either firm in 2010). Bristol was close behind with two first-half approvals, both for therapeutic biologics (for complete approval listings, see Also see "New Molecular Entities Approved In 2011" - Pink Sheet, 1 July, 2011. and Also see "Biologics Approved In 2011" - Pink Sheet, 1 July, 2011.).

That’s a pretty sharp contrast to big pharma’s showing in 2010, when for the whole year only Novartis received multiple approvals, and only two at that. Specialty firms were the most significant contributors to the 2010 approval totals Also see "The Return Of Big Pharma? 2011 Novel Approvals Could Show Payoff Of Licensing And Acquisition Strategies" - Pink Sheet, 1 February, 2011.)

Specialty firms definitely had a presence – notably Forest Laboratories, which received approval for Daliresp (roflumilast). Forest also acquired Clinical Data Inc. and its Trovis subsidiary, which holds the NDA for one of FDA’s first approvals of 2011, the antidepressant Viibryd (vilazodone), and followed up with an NDA submission announced June 30 for another respiratory NME, the COPD therapy aclidinium.

Hospital product specialist Optimer Pharmaceuticals brought its first drug to market, Dificid (fidaxomicin), an antibiotic for C. difficile infection. Optimer had to navigate an anti-infectives landscape still recovering from a period of many "complete response" letters and few antibiotic NME approvals as FDA worked to implement new policy, particularly regarding non-inferiority margins.

ParaPRO received approval for its first product, the topical head lice treatment Natroba (spinosad), based on an active ingredient licensed from Lilly in November 2002. Pediatric specialty firm Pernix Therapeutics is co-promoting the drug.

Venerable small molecule boutique Vertex Pharmaceuticals shepherded its breakthrough hepatitis C therapy Incivek (telaprevir) to approval within two weeks of Merck’s competing protease inhibitor Victrelis (boceprevir), the big pharma's first (and to date only) NME of the year. Biologics specialist CSL Behring got approval of another orphan blood factor concentrate. Autologous cell treatment firm Fibrocell Sciences received its first approval for an aesthetic agent.

The remaining 2011 pending NMEs and BLAs also have a strong big pharma flavor, with products from AstraZeneca (anticoagulant Brilinta and partnered with Bristol, the first-in-class antidiabetic dapagliflozin), Roche (with the Genentech/Plexxikon oncologic vemurafenib), Merck (eye drug tafluprost with Santen) and Pfizer (oncologic crizotinib, plus an outside possibility for the oncologic axitinib, which has an early 2012 goal date).

But smaller specialty firms could also make a mark in the latter half of the year and several of those are significant scientific advances. Regeneron’s first submission, the fusion protein VEGF Trap-Eye, or Eylea (aflibercept), received a unanimous advisory committee recommendation for wet AMD. Incyte has the first in the highly anticipated JAK inhibitor class up for approval with ruxolitinib for myelofibrosis. And Seattle Genetics just received an advisory committee endorsement for its pioneering antibody-drug conjugate, brentuximab vedotin, for two forms of lymphoma.

By Bridget Silverman, ,

FDA Sets A Fast Pace Of Novel Approvals In First Half, But That's Likely To Slow

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